TRANSITION METAL COMPLEXES AS DRUGS AND CHEMOTHERAPEUTIC AGENTS

Transcription

1 TRANSITION METAL COMPLEXES AS DRUGS AND CHEMOTHERAPEUTIC AGENTS

2 CATALYSIS BY METAL COMPLEXES Editors R. UGO, University of Mila n, Milan, Italy B. R. JAM E S, University of British Columbia, Vancouver, Canada Advisory Board J. L. G ARNE TT, University of New South Wales, Kensington, Australia L. MARKO, Hungarian Academy of Sciences, Veszprem, Hungary ICHIRO MORIT ANI, Osaka University, Osaka, Japan W. ORME-JOHNSON, Massachusetts Institute of Technology, Cambridge, Mass., u.s.a. R. L. RICHARDS, University of Sussex, Brighton, England C. A. TOLMAN, E. I. du Pont de Nemours Co., Inc., Wilmington, Del., U.S.A. VOLUME 11

3 TRANSITION METAL COMPLEXES AS DRUGS AND CHEMOTHERAPEUTIC AGENTS by NICHOLAS FARRELL The University of Vermont, Burlington, Vermont, U.S.A. KLUWER ACADEMIC PUBLISHERS DORDRECHT / BOSTON / LONDON

4 Library of Congress Cataloging-in-Publication Data Farrell. N1cholas. Trans1t1on metal complexes as drugs and chemother~peut1c by N1cholas Farrell. p. em. -- (Catalysis by metal complexes) Inc 1 udes j ndex. agents 1. Trans1t1on metal complexes--therapeutic use--test1ng. 2. Transition metal complexes--physiolog1cal effect. I. Title. II. Series. [DNLM: 1. Metals--pharmacokinetics. 2. Metals--therapeutic use. au 30 F245tl RM666.T74F '.26--dc19 DNLM/DLC for L1brary of Congress TSBN-13: DOT: / e-tsbn-13: Published by Kluwer Academic Publishers, P.O. Box 17, 3300 AA Dordrecht, The Netherlands. Kluwer Academic Publishers incorporates the publishing programmes of D. Reidel, Martinus Nijhoff, Dr W. Junk and MTP Press. Sold and distributed in the U.S.A. and Canada by Kluwer Academic Publishers, 101 Philip Drive, Norwell, MA 02061, U.S.A. In all other countries, sold and distributed by Kluwer Academic Publishers Group, P.O. Box 322, 3300 AH Dordrecht, The Netherlands. All Rights Reserved 1989 Kluwer Academic Publishers No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner.

5 CONTENTS PREFACE xli INTRODUCTION 1 Metals in Medicine 2 Chemotherapeutic Agents and Drugs 4 Mechanisms of Toxicity 4 Metal Accumulation and Activation 4 Biochemical Targets for Metal Complexes 5 ~~~ 6 References 6 CHAPTER 1. Interaction of Metal Complexes with DNA DNA and Conformation Nucleases and DNA Experimental Methods for the Study of Conformational Changes Ultraviolet Spectroscopy Circular Dichroism and Optical Dispersion Nuclear Magnetic Resonance Hydrodynamic and Light Scattering Properties Binding of Metal Complexes to DNA Intercalation Platinum-Terpyridine Complexes Metal-(1,10-Phenanthroline) Complexes Porphyrins and Metalloporphyrins Intercalators as Drugs Redox Activity of Metallointercalators Outer Sphere Binding Metal-Amine Complexes Inner Sphere (Covalent) Binding Binding of Platinum-Amine Complexes 30 v

6 VI CONTENTS Platinum-Amine Complexes and Intercalators Restriction Enzymes and Platinum Complexes Strand Breakage Copper-(1,10-phenanthroline) Complexes Cobalt-(1,10-phenanthroline) Complexes Iron-EDTA-(DNA-binder) Complexes Summary 40 References 40 CHAPTER 2. Platinum-Amine Complexes as Anticancer Agents 2.1. The Discovery of Cisplatin as an Antitumour Agent Clinical Properties of Cisplatin Development of Cisplatin Analogues Clinical trials of Cisplatin Analogues Biochemical Mechanism of Action of Platinum Complexes Biological Effects Implying DNA as Target Biological Effects not Involving DNA Summary 62 References 63 CHAPTER 3. Structure-Activity Relationships of Platinum- Amine Complexes The Requirement for Neutrality Complexes of Pt(IV) Nature of the Leaving Group Bisplatinum Complexes Containing Bridging Dicarboxylates Sulfoxides as Leaving groups Nature of the Nonleaving Group Stereospecific Effects in Amine Complexes Novel and Targeted Approaches to [ptx2(amhl Complexes Ternary Complexes Amines as Carrier Ligands Quantitative Structure-Activity Relationships Chemistry of Platinum-Amine Complexes Reactions with Biomolecules Other Than DNA Summary 90 References 90

7 CONTENTS vil CHAPTER 4. Interactions of Platinum Complexes with DNA Components Structural Aspects of Metal-Nucleobase Binding Binding in Solution Basicity and ph Hard-Soft Relationship of Donor Atom and Metal Ion Steric Effects Including Hydrogen Bonding Base Stacking and Chelation Binding of Platinum Complexes in Solution Reactivity of Platinum Metal-Base Complexes Effect of Metallation on Acidity of Noncoordinated Atoms The Platinum-N 7, 0 6 Chelate Effect of Metallation on C-H Exchange Susceptibility to Oxidation of Metal-Base Complexes Reactivity of Nucleoside and Nucleotide Linkages Reactivity of Metal-Base Complexes toward Nucleophiles Linkage Isomerization Rotation around Metal-Purine Bonds Solid State Structural Studies Structural Studies on Di- and Oligonucleotide Complexes Studies on Dinucleotide Complexes Studies on Trinucleotides Studies on Oligonucleotides Structural Studies on Oligonucleotides Platinum Adducts from DNA Degradation On the Molecular Mechanism of Antitumour Action of Cisplatin Summary 121 References 121 CHAPTER 5. The Platinum-Pyrimidine Blues Properties ofthe Platinum-Pyrimidine Blues Platinum Blues not Derived from Pyrimidines X-Ray Structure of Platinum-Pyrimidine and a- Pyridone Blues Formation of Platinum-Pyrimidine and a-pyridone Blues 131

8 viii CONTENTS Monomeric Complexes Dimeric Complexes Complexes of Pt(III) Studies of Crystalline Blues Biological Studies on Platinum-Pyrimidine Blue Precursors 5.7. Summary References CHAPTER 6. Antitumour Activity of Metal Complexes 6.1. Platinum Group Metal Complexes Palladium Complexes Rhodium Complexes Studies on Rhodium Carboxylates Ruthenium Complexes Studies on Ruthenium-Amine Complexes 6.2. Copper Complexes Bis(Thiosemicarbazone) Complexes Thiosernicarbazone Complexes Nitrogen Chelates Copper Salicylates 6.3. Silver and Gold 604. Organometallic Complexes 6.5. Summary References CHAPTER 7. Metal-Mediated Antibiotic Action 7.1. Discovery and Pharmacology of Bleomycin 7.2. Structure of Bleomycin and Analogues 7.3. Metal Complexes of Bleomycin Copper Bleomycin Cobalt Bleomycin Manganese Bleomycin 7 A. Mechanism of Action of Bleomycin DNA-Bleomycin Interactions Iron and Iron-Oxygen Adducts 7.5. Other Metal Binding Antibiotics Anthracyclines Biochemical Aspects of Metal-Anthracyclines Streptonigrin 7.6. Summary References

9 CONTENTS ~ CHAPTER 8. Metals, Metal Complexes, and Radiation Interaction of Radiation and Biological Tissue Chemical Modification of Radiation Damage Oxygen Mimics and Electron Affinity Metal Complexes as Radiation Sensitizers Radiosensitization by Metal Salts Cobalt-Amine Complexes Radiosensitization by Electron Affinity Metal-Radiosensitizer Complexes Metal Chelates Potentiation of Radiation Damage by Platinum-Amines. Differential Repair Processes Mechanism of Action of Platinum-Amine Complexes Radiosensitization by Thiol Depletion Metal Complexes and Radioprotection Metal Complexes as Radioprotectors Activation of Metal Complexes Summary 203 References 204 CHAPTER 9. Antibacterial Effects of Metal Complexes Mercury and Silver Salts as Antibacterial Agents Mercury Silver Antibacterial Activity of Chelating Agents and Metal Chelates Antibacterial Activity of Metal-Amine Complexes Redox Activity and Antibacterial Activity Summary 219 References 220 CHAPTER 10. Antiviral and Antiparasitic Effects of Metal Complexes Antiviral Therapy Chelating Agents and Metal Complexes as Antiviral Agents ChelatingAgents Metal-(1,10-Phenanthroline) Complexes Platinum- and Palladium-Amine Complexes Zinc Complexes Other Metal Complexes Metal Complexes as Antiprotozoal Agents 230

10 x CONTENTS Metal Complexes in Trypanosomiasis Platinum-Amine Complexes as Trypanocides Other Metal Complexes Porphyrins and Metalloporphyrins as Trypanocides. Metal Sequestration Metal Complexes with Trypanocidal Drugs. Dual-Function Agents Metal Complexes in American Trypanosomiasis Summary 239 References 239 CHAPTER 11 Metal Complexes in Arthritis Gold Complexes in the Treatment of Rheumatoid Arthritis Activity and Toxicity of Gold Drugs Structures of Gold Complexes Chemistry and Biochemistry of Gold Drugs Mechanism of Action of Gold Drugs Copper in Arthritis Copper Complexes in Arthritis Copper Bracelets Coppef'and D-Penicillamine Mechanism of Action of Copper Complexes Other Metals Summary 252 References 253 CHAPTER 12. Miscellaneous Uses of Metal Complexes Mercurial Diuretics Neuromuscular Effects of Metal Complexes Nitroprusside as Vasodilator Activity and Toxicity of Nitroprusside Mechanism of Action of Nitroprusside Summary 263 References 263 NAMES AND ABBREVIATIONS 266 GLOSSARY OF TERMS AND DEFINITIONS 270 APPENDIX 1 274

11 CONTENTS Xl APPENDIX 2 INDEX OF SUBJECTS

12 PREFACE When this book was first conceived as a project the expanding interest in the clinical use of platinum and gold complexes made a survey of the relevant biological properties of metal complexes timely and appropriate. This timeliness has not diminished during the gestation and final publication of the manuscript. The introduction contains an explanation of the layout and approach to the book, which I wrote as an overall survey of the wide variety of biological properties of metal complexes. Hopefully, the reader will see the parallels in mechanisms and behavior, even in different organisms. The writing was considerably helped by the enthusiasm and confidence (totally unearned on my part) in the project of Professor Brian James and lowe him my special thanks. I also owe a great debt of gratitude to my colleagues, and especially to Eucler Paniago, of the Universidade Federal de Minas Gerais, for their comprehension and for the initial leave of absence which allowed me to begin the project. To those who read some or all of the manuscript and made suggestions, Bernhard Lippert, Kirsten Skov, and Tom Tritton, as well as the editor's reviewer I am also grateful. As usual, the final responsibility for errors or otherwise rests with the author. NICHOLAS FARRELL xii